Restricting calories is known to improve health, increase lifespan and protect the brain, but much of how it does that has remained a mystery. But now, a team of scientists at Buck Institute for Research on Ageing in California say they’ve found a gene that’s not only necessary for lifespan extension that comes with dietary restriction but is also essential for healthy brain ageing.
“When people restrict the amount of food they eat, they typically think it might affect their digestive tract or fat buildup, but not necessarily about how it affects the brain,” says Kenneth Wilson, Ph.D., Buck postdoc and first author of the study, published in Nature Communications. “As it turns out, [there] is a gene that is important in the brain.”
Using fruit flies and human cells, the team has demonstrated a detailed cellular mechanism of how dietary restriction can delay ageing and slow the progression of neurodegenerative diseases.
“We found a neuron-specific response that mediates the neuroprotection of dietary restriction,” says Buck Professor Pankaj Kapahi, Ph.D., co-senior author of the study. “Strategies such as intermittent fasting or caloric restriction, which limit nutrients, may enhance levels of this gene to mediate its protective effects.”
Buck Institute researchers had already shown that dietary restriction improves lifespan and healthspan, but because everyone is different and responds differently to reduced calories, there are many yet to be discovered processes in play. (The project started out attempting to understand why different people respond to diets in different ways.)
After a series of in-depth tests, the team found a gene called OXR1 that affects the retromer, a set of proteins necessary for recycling cellular proteins and lipids. “The retromer is an important mechanism in neurons because it determines the fate of all proteins that are brought into the cell,” says Wilson. Retromer dysfunction has been associated with age-related neurodegenerative diseases, specifically Alzheimer’s and Parkinson’s diseases.
Overall, their results show how dietary restriction slows brain ageing; put simply, OXR1 maintains the retromer in humans.
“Diet is influencing this gene. By eating less, you are actually enhancing this mechanism of proteins being sorted properly in your cells, because your cells are enhancing the expression of OXR1,” says Wilson.
The team speculates that excess expression of OXR1 might help extend lifespan. “Our next step is to identify specific compounds that increase the levels of OXR1 during ageing to delay brain ageing,” says Buck Professor Lisa Ellerby, Ph.D., co-senior author of the study.
"Hopefully from this we can get more of an idea of why our brains degenerate in the first place. Diet impacts all the processes in your body,” Wilson notes. “I think this work supports efforts to follow a healthy diet, because what you eat is going to affect more than you know.”